Triazole derivatives and salts thereof and antifungal agent containing the same

ABSTRACT

The present invention relates to a compound represented by the general formula (1) or its salt, a process for producing the same, and an antifungal agent comprising the same as an effective component: ##STR1## wherein R 1  represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group bonded through a carbon atom in the ring to the main chain; R 2  presents a hydrogen atom, a fluorine atom or a substituted or unsubstituted alkyl group; and R 3  represents a cyano group, a thioamido group or a group represented by the formula ##STR2## in which R 4  is a hydroxyl group or a group of the formula ##STR3## (R 7  and R 8 , which may be the same or different, are hydrogen atoms or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, amino, alkoxy, hydroxyl or heterocyclic groups, and may form a substituted or unsubstituted heterocyclic group together with the nitrogen atom to which R 7  and R 8  attach), R 5  is a substituted or unsubstituted alkoxy group or a group of the formula ##STR4## (R 7  and R 8  are as defined above), and R 6  is a hydrogen atom or a substituted or unsubstituted alkyl group.

The present invention relates to a novel triazole derivative or a salt thereof, a process for producing the same, and an antifungal agent containing the same.

Currently, Amphotericin B (disclosed in U.S. Pat. No. 2,908,611) and Flucytosine (disclosed in U.S. Pat. No. 2,802,005) are mainly used as remedies for deep mycosis. Further, Ketoconazole (disclosed in Japanese Patent Application Kokai (Laid-Open) No. 53-95973), Fluconazole (disclosed in Japanese Patent Application Kokai (Laid-Open) No. 58-32868), etc. are on the market as azole type antifungal agents. They are useful remedies for mycosis.

The above remedies, however, are not satisfactory in view of pharmacokinetics, toxicity, broad antifungal spectrum, etc. Hence, it has been desired to develop a more effective compound.

Under such circumstances, the present inventors have made extensive research and, as a result, found that the compound of the present invention has an excellent antifungal activity and exhibits an excellent therapeutic effect.

An object of the present invention is to provide a novel triazole derivative or a salt thereof.

Another object of the present invention is to provide a novel triazole derivative or a salt thereof, each having an excellent antifungal activity, being excellent in absorbability and exhibiting excellent pharmacokinetics.

Still another object of the present invention is to provide a process for producing a novel triazole derivative or a salt thereof.

A further object of the present invention is to provide an antifungal agent containing a novel triazole derivative or a salt thereof, each useful for the treatment of mycosis.

Other objects and advantages of the present invention will become apparent from the following description.

According to the present invention, there is provided a triazole derivative represented by the general formula (1) or a salt thereof: ##STR5## wherein R¹ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group bonded through a carbon atom in the ring to the main chain; R² represents a hydrogen atom, a fluorine atom or a substituted or unsubstituted alkyl group; and R³ represents a cyano group, a thioamido group or a group represented by the formula ##STR6## in which R⁴ is a hydroxyl group or a group of the formula ##STR7## (R⁷ and R⁸, which may be the same or different, are hydrogen atoms or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, amino, alkoxy, hydroxyl or heterocyclic groups, and may form a substituted or unsubstituted heterocyclic group together with the nitrogen atom to which R⁷ and R⁸ attach), R⁵ is a substituted or unsubstituted alkoxy group or a group of the formula ##STR8## (R⁷ and R⁸ are as defined above), and R⁶ is a hydrogen atom or a substituted or unsubstituted alkyl group.

The compound of the present invention is hereinafter described in detail.

In the present specification, unless otherwise specified, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom: the alkyl group means a straight chain or branched chain C₁₋₁₀ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl or the like; the alkenyl group means a straight chain or branched chain C₂₋₁₀ alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl or the like; the alkynyl group means a straight chain or branched chain C₂₋₁₀ alkynyl group such as ethynyl, propynyl, butynyl, pentynyl, hexynyl or the like; the alkoxy group means a C₁₋₁₀ alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or the like; the lower alkoxycarbonyl group means a C₁₋₄ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, secbutoxycarbonyl, tert-butoxycarbonyl or the like; the alkylthio group means a C₁₋₁₀ alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio or the like; the aryl group means a phenyl or naphthyl group; the cycloalkyl group means a C₃₋₈ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl or the like; the halo-lower alkyl group means a halogen atom-substituted C₁₋₄ alkyl group such as fluoromethyl, chloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1,1,2,2,3,3,3-heptafluoropropyl or the like; the halo-lower alkoxy group means a halogen-substituted C₁₋₄ alkoxy group such as fluoromethoxy, chloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 1,1,2,2,3,3,3 -heptafluoropropoxy or the like; the N-lower alkylamino group means an N--C₁₋₄ alkylamino group such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino or the like; the N,N-di-lower alkylamino group means an N,N-di-C₁₋₄ alkylamino group such as dimethylamino, diethylamino, dipropylamino, methylethylamino or the like; the acyl group means a formyl group, a C₂₋₁₀ alkanoyl group such as acetyl, ethylcarbonyl or the like, or an aroyl group such as benzoyl, naphthylcarbonyl or the like; and "lower" means a group having 1-4 carbon atoms.

In the definition of R¹, the heterocyclic group bonded through a carbon atom in the ring to the main chain of the triazole derivative includes five- and six-membered heterocyclic groups each containing at least one oxygen, sulfur or nitrogen atom, such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2H-pyran-3-yl, pyrrol-3-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-3-yl, isoxazol-3-yl, pyridin-2-yl, pyridin-3-yl, 1-oxidopyridin-3-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrrolidin-2-yl, 2-pyrrolin-3-yl, imidazolidin-2-yl, 2-imidazolin-4-yl, piperidin-2-yl, morpholin-3-yl and the like.

In the definitions of R⁷ and R⁸, the heterocyclic group includes five- and six-membered heterocyclic groups each containing at least one oxygen, sulfur or nitrogen atom, such as thienyl, furyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, iso-thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. The substituted or unsubstituted heterocyclic group which R⁷ and R⁸ form together with the nitrogen atom to which R⁷ and R⁸ attach, includes three- to six-membered nitrogen-containing heterocyclic groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.

Each of the substituted aryl group and the substituted heterocyclic group bonded through a carbon atom in the ring to the main chain in the definition of R¹ ; the substituted alkyl group in the definitions of R² and R⁶ ; the substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, amino, alkoxy, hydroxyl and heterocyclic groups in the definitions of R⁷ and R⁸ ; the substituted heterocyclic group which R⁷ and R⁸ form together with the nitrogen atom to which R⁷ and R⁸ attach in the definitions of R⁷ and R⁸ ; and the substituted alkoxy group in the definition of R⁵ has at least one substituent selected from the group consisting of halogen atoms, unsubstituted or cyano-substituted lower alkyl groups, lower alkoxy groups, halo-lower alkoxy groups, lower alkylthio groups, lower alkoxycarbonyl groups, hydroxyl group, mercapto group, carboxyl group, amino group, N-lower alkylamino groups, N,N-di-lower alkylamino groups, cyano group, nitro group, halo-lower alkyl groups, unsubstituted or halogen-substituted aryl groups, unsubstituted or halogen-substituted acyl groups and unsubstituted or alkyl-, cycloalkyl- or aryl-substituted carbamoyl groups.

Of the compounds of the general formula (1), preferable are those compounds wherein R¹ is a halogen-substituted phenyl group, R² is a fluorine atom, and R³ is a group of the formula ##STR9## (one of R⁷ and R⁸ is a hydrogen atom and the other is a hydrogen atom, a lower alkyl group or a cyclopropyl group); more preferable are those compounds wherein R¹ is a 2,4-difluorophenyl group or a 2-chloro-4-fluorophenyl group, R² is a fluorine atom, and R³ is a group of the formula ##STR10## (one of R⁷ and R⁸ is a hydrogen atom and the other is a hydrogen atom, a methyl group or a cyclopropyl group), or optically active compounds corresponding thereto.

The salt of the compound of the general formula (1) includes pharmaceutically acceptable salts, for example, salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; salts with carboxylic acids such as acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, oxalic acid, aspartic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like.

The compound of the present invention further includes all geometrical and optical isomers, hydrates and solvates, and also includes all crystal forms.

The novel triazole derivative of the general formula (1) and its salt can generally be produced by a process known per se or a combination thereof. They can be produced by, for example, one of following Processes 1 to 8: ##STR11## wherein X represents a removable group, for example, a halogen atom; a lower alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy or the like; or an unsubstituted or halogen- or lower-alkyl-substituted arylsulfonyloxy group such as benzenesulfonyloxy, tosyloxy, p-chlorobenzenesulfonyloxy or the like, and R¹, R², R⁷ and R⁸ have the same meanings as defined above. ##STR12## wherein R⁹ represents a lower alkyl group; and R¹, R², R⁷ and R⁸ have the same meanings as defined above. ##STR13## wherein R¹, R², R⁷ and R⁸ have the same meanings as defined above. ##STR14## wherein R¹ and R² have the same meanings as defined above. ##STR15## wherein --OR¹⁰ represents a substituted or unsubstituted alkoxy group which is the same as mentioned in the definition of R⁵ ; and R¹ and R² have the same meanings as defined above. ##STR16## wherein R¹, R², R⁷, R⁸ and --OR¹⁰ have the same meanings as defined above. ##STR17## wherein R¹, R² and R⁶ have the same meanings as defined above. ##STR18## wherein R¹ and R² have the same meanings as defined above.

Next, the processes for producing a novel triazole derivative of the general formula (1) or its salt are described in detail, based on Processes 1-8.

Process 1

The compound of the general formula (1a) or its salt can be produced by reacting a compound of the general formula (2) or (3) with a 1,2,4-triazole or its salt.

The salt of the compound of the general formula (1a) includes the same salts as mentioned as to the compound of the general formula (1).

The salt of 1,2,4-triazole includes, for example, salts with alkali metals such as potassium, sodium and the like; and salts with organic bases such as triethylamine, tributylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and the like. These salts may also be formed in situ.

The reaction can be conducted in the presence or absence of a solvent. The solvent may be any solvent as long as it does not adversely affect the reaction, and it includes amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; alcohols such as methanol, ethanol and the like; ethers such as diethyl ether, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene and the like; nitriles such as acetonitrile and the like; dimethyl sulfoxide; sulfolane; water; etc. These solvents may be used alone or in admixture of two or more.

The amount of 1,2,4-triazole or its salt used is 1 mole or more per mole of the compound of the general formula (2) or (3).

The reaction is preferably conducted at 20°-150° C. for 0.5-24 hours.

Process 2

The compound of the general formula (1a) or its salt can be produced by reacting a compound of the general formula (4) or its salt with a compound of the general formula (5) or its salt.

The salts of the compounds of the general formulas (4) and (5) include the same salts as mentioned as to the compound of the general formula (1).

The reaction can be conducted in the presence or absence of a solvent. The solvent may be any solvent as long as it does not adversely affect the reaction, and it includes ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; alcohols such as methanol, ethanol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; dimethyl sulfoxide; water; etc. These solvents may be used alone or in admixture of two or more.

It is also possible to use the compound of the general formula (5) or its salt as a solvent.

The amount of the compound of the general formula (5) or its salt used is 1 mole or more per mole of the compound of the general formula (4) or its salt.

The reaction is preferably conducted at -20° to 200° C. for 0.5-24 hours.

Process 3

The compound of the general formula (1a) or its salt can be produced by subjecting a compound of the general formula (4) or its salt to conventional hydrolysis to convert it to a compound of the general formula (1b) or its salt, activating it by a known method to convert it to a reactive derivative of the compound of the general formula (1b) or its salt, then reacting the reactive derivative with a compound of the general formula (5) or its salt in the same manner as in Process 2.

The salt of the compound of the general formula (1b) includes the same salts as mentioned as to the compound of the general formula (1) and salts with alkali metals such as potassium, sodium and the like.

The reactive derivative of the compound of the general formula (1b) includes acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, reactive derivatives derived from Vilsmeier reagent, etc.

Process 4

The compound of the general formula (1d) or its salt can be produced by reacting a compound of the general formula (1c) or its salt with a dehydrating agent.

The salts of the compounds of the general formulas (1c) and (1d) include the same salts as mentioned as to the compound of the general formula (1).

The dehydrating agent includes acetic anhydride, benzoyl chloride, trichloroacetyl chloride, thionyl chloride, phosphorus pentoxide, etc.

The reaction can be conducted in the presence or absence of a solvent. The solvent may be any solvent as long as it does not adversely affect the reaction, and includes ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; pyridine; etc. These solvents may be used alone or in admixture of two or more.

The reaction is preferably conducted at 0°-150° C. for 0.1-24 hours.

Process 5

The compound of the general formula (1e) or its salt can be produced by reacting a compound of the general formula (1d) or its salt with a compound of the general formula (6).

The salt of the compound of the general formula (1e) includes the same salts as mentioned as to the compound of the general formula (1).

The amount of the compound of the general formula (6) used is 1 mole or more per mole of the compound of the general formula (1d) or its salt. It is preferable to use the compound of the general formula (6) as a solvent.

In the reaction, there may be used a solvent which does not adversely affect the reaction. The solvent includes ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene and the like; and halogenated hydrocarbons such as methylene chloride, chloroform and the like. These solvents may be used alone or in admixture of two or more.

The reaction is preferably conducted at 0°-100° C. for 0.1-24 hours.

Process 6

The compound of the general formula (1f) or its salt can be produced by reacting a compound of the general formula (1e) or its salt or a compound of the general formula (1d) or its salt with a compound of the general formula (5) or its salt.

The salt of the compound of the general formula (1f) includes the same salts as mentioned as to the compound of the general formula (1).

The reaction can be conducted in the presence or absence of a solvent. The solvent may be any solvent as long as it does not adversely affect the reaction, and includes ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol and the like; aromatic hydrocarbons such as benzene, toluene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; etc. These solvents may be used alone or in admixture of two or more.

It is also possible to use the compound of the general formula (5) or its salt as a solvent.

The amount of the compound of the general formula (5) or its salt used is 1 mole or more per mole of the compound of the general formula (1e) or its salt or the compound of the general formula (1d) or its salt.

The reaction is preferably conducted at 0°-150° C. for 0.5-24 hours.

Process 7

The compound of the general formula (1g) or its salt can be produced by reacting a compound of the general formula (1d) or its salt with a compound of the general formula (7) or its salt.

The salts of the compounds of the general formulas (7) and (1g) include the same salts as mentioned as to the compound of the general formula (1).

The reaction can be conducted in the same manner as in Process 6.

A deacidifying agent may be used if necessary. The deacidifying agent includes amines such as triethylamine and the like.

Process 8

The compound of the general formula (1h) or its salt can be produced by reacting a compound of the general formula (1d) or its salt with diethyl dithiophosphate in the presence of water.

The salt of the compound of the general formula (1h) includes the same salts as mentioned as to the compound of the general formula (1).

The amount of diethyl dithiophosphate used is 1 mole or more per mole of the compound of the general formula (1d) or its salt.

The reaction is preferably conducted at 0°-150° C. for 0.5-10 hours.

Next, a description is made on the processes for production of the compound of the general formula (2) or (3) or the compound of the general formula (4) or its salt, which are the starting materials for the production of the compound of the present invention.

The compound of the general formula (2) or (3), or the compound of the general formula (4) or its salt can be produced by, for example, processes A-D described below. ##STR19## wherein Y represents a halogen atom; and R¹, R², R⁷, R⁸, R⁹ and X have the same meanings as defined above. ##STR20## wherein R¹, R², R⁷, R⁸ and R⁹ have the same meanings as defined above. ##STR21## wherein R¹, R², R⁹ and Y have the same meanings as defined above. ##STR22## wherein R¹, R² and R⁹ have the same meanings as defined above.

The processes for the production of the compound of the general formula (2) or (3), or the compound of the general formula (4) or its salt are described in detail below, based on Processes A-D.

Process A

The compound of the general formula (8) can be produced according to known methods or methods similar thereto, for example, the methods described in Org. Synth. I, 109 and II, 480 and Japanese Patent Application Kokai (Laid-Open) No. 58-32868.

Each step of this process is described below.

(i) Production of compound of the general formula (10) or (11)

The compound of the general formula (10) or (11) can be produced by reacting a compound of the general formula (8) with a compound of the general formula (9a) or with a compound of the general formula (9b) and zinc.

This reaction can be conducted according to, for example, the method described in Tetrahedron Lett. 25, 2301 (1984) or Japanese Patent Application Kokai (Laid-Open) No. 59-82376 or 62-249978.

The compound of the general formula (11) can also be produced by reacting the compound of the general formula (10) with a base.

The base includes organic bases such as triethylamine, tributylamine, DBU and the like, and inorganic bases such as potassium carbonate, sodium hydroxide and the like.

(ii) Production of compound of the general formula (2) or (3)

The compound of the general formula (2) or (3) can be produced by reacting the compound of the general formula (10) with a compound of the general formula (5) or its salt.

The compound of the general formula (3) can also be produced by reacting the compound of the general formula (11) with the compound of the general formula (5) or its salt.

These reactions can be conducted in the same manner as in Process 2.

Process B

The compound of the general formula (3) can be produced by subjecting a compound of the general formula (11) to conventional hydrolysis to convert it to a compound of the general formula (12), activating the compound of the general formula (12) by a known method to convert it to a reactive derivative of the compound of the general formula (12), then reacting the reactive derivative with a compound of the general formula (5) or its salt.

This reaction can be conducted in the same manner as in Process 3.

Process C

The compound of the general formula (13) can be produced according to a known method or a method similar thereto, for example, the method described in Japanese Patent Application Kokai (Laid-Open) No. 58-32868 or 59-62575.

The compound of the general formula (4) or its salt can be produced by reacting the compound of the general formula (13) with a compound of the general formula (9a) or with a compound of the general formula (9b) and zinc.

This reaction can be conducted in the same manner as in (i) of Process A.

Process D

The compound of the general formula (4) or its salt can be produced by reacting a compound of the general formula (11) with 1,2,4-triazole or its salt.

This reaction can be conducted in the same manner as in Process 1.

The compound of the general formula (1) or its salt thus obtained can be isolated and purified by conventional methods such as extraction, crystallization, distillation, column chromatography and the like.

The compound of the general formula (1) or its salt can be converted to other desired compounds of the general formula (1) or their salts, by using an appropriate combination of methods known per se such as oxidation, reduction, addition, alkylation, acylation, cyclization, substitution, deprotection, hydrolysis and the like.

When the compound of the present invention is used as a drug or medicine, it is appropriately combined, if necessary, with pharmaceutically acceptable additives such as excipient, carrier, diluent and the like. The resulting mixture is molded into forms such as tablets, capsules, granules, parvules, powder, injection and the like according to a conventional method, and can be administered orally or parenterally. The dose is, in the case of oral administration, preferably about 0.05-200 mg/kg/day of adult body weight. This daily dose may be administered in one or several portions. The dose and number of portions of administration can be appropriately varied depending upon the age, weight and disease condition of patient.

Next, a description is made on the pharmacological actions of the representative compounds of the present invention.

1. Minimum inhibitory concentration (MIC)

MIC was determined in accordance with the method of M.S. Marriott [25th Interscience Conference on Antimicrobial Agents and Chemotherapy, p. 243 (1985)].

Candida albicans ON28 was cultured in a sabouraud dextrose agar medium containing 10 g of neopeptone, 20 g of glucose and 15 g of agar per liter, at 30° C. for 1-2 days. The yeast cells were suspended in sterile distilled water. Separately, Aspergillus fumigatus IFO8868 was cultured in a potato dextrose agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.) at 30° C. until the conidia were formed abundantly. The formed conidia were suspended in a sterile physiological saline containing 0.1% of Tween 80. Each of the Candida albicans suspension and the Aspergillus fumigatus suspension was inoculated into a TC broth medium (containing 1.17 g of an yeast carbon base, 0.25 g of ammonium sulfate, 2.0 ml of a 50-fold concentrate of L-glutamic acid-containing MEM amino acid, 20 ml of a 0.5M phosphate buffer of pH 7.5 and 1.33 ml of 7.5% sodium hydrogencarbonate per 100 ml) containing a test compound, so that the final fungal amount became 10⁴ spores/ml. Then, culture was conducted at 37° C. for 3 days. Thereafter, the growth of fungi was examined. The minimum concentration of test compound at which the growth of fungi had been inhibited, was taken as MIC (μg/ml).

The results are shown in Table 1.

                  TABLE 1                                                          ______________________________________                                         Example    Candida albicans                                                                            Aspergillus                                            No.        ON28         fumigatus IFO8868                                      ______________________________________                                          3         0.39         12.5                                                    4         0.1          50                                                      5         ≦0.05 12.5                                                    8         0.78         25                                                     11         0.2          100                                                    12         0.2          25                                                     16         ≦0.05 25                                                     17         0.1          12.5                                                   19         0.1          50                                                     20         ≦0.05 100                                                    21         ≦0.05 100                                                    22         ≦0.05 12.5                                                   30         0.2          12.5                                                   33         0.2          50                                                     35         ≦0.05 25                                                     39         6.25         100                                                    42         ≦0.05 50                                                     43         ≦0.05 25                                                     44         ≦0.05 1.56                                                   45         ≦0.05 50                                                     51         0.1          12.5                                                   56         0.39         100                                                    69         0.39         50                                                     72         0.39         50                                                     73         0.39         25                                                     74         0.78         12.5                                                   75         0.2          6.25                                                   79         0.78         50                                                     80         0.39         12.5                                                   81         0.1          3.13                                                   83         0.1          25                                                     85         0.1          12.5                                                   88         0.2          50                                                     114        0.05         12.5                                                   117        0.39         25                                                     136        0.025        12.5                                                   138        0.1          12.5                                                   139        0.05         12.5                                                   142        0.78         100                                                    143        0.2          25                                                     144        0.1          6.25                                                   145        0.1          12.5                                                   146        0.39         50                                                     147        0.1          6.25                                                   148        0.1          3.13                                                   ______________________________________                                    

2. Therapeutic effect

(1) The therapeutic effects of the present compounds, when they were administered orally, were examined using mice infected with Candida albicans ON28.

Candida albicans ON28 was injected in a proportion of 3.5×10⁶ cells/mouse to a group of 5 ICR strain male mice (weight: 19-21 g) intravenously at the tails, whereby the mice were infected with the fungi. Two hours after the infection, a test compound was orally administered in a proportion of 0.1 mg/mouse to the mice, and their survival was observed for 10 days. The relative therapeutic index of the test compound was determined from the average survival days.

The results are shown in Table 2a, in which the relative therapeutic index of each test compound is a value calculated by taking the average survival days Ketoconazole as 100.

                  TABLE 2a                                                         ______________________________________                                         Example No.  Relative therapeutic index                                        ______________________________________                                         12           440                                                               19           625                                                               30           355                                                               ______________________________________                                    

(2) The therapeutic effects of the present compounds, when they were administered orally, were examined using mice infected with Aspergillus fumigatus IFO8868.

Aspergillus fumigatus IFO8868 was injected in a proportion of 3.6×10⁶ cells/mouse to a group of 5 ICR strain male mice (weight: 19-21 g) intravenously at the tails, whereby the mice were infected with the fungi. Two hours after the infection, a test compound was orally administered in a proportion of 0.8 mg/mouse to the mice, and their survival was observed for 10 days. The relative therapeutic index of the test compound was determined from the average survival days.

The results are shown in Table 2b, in which the relative therapeutic index of each test compound is a value calculated by taking the average survival days of Ketoconazole as 100.

                  TABLE 2b                                                         ______________________________________                                         Example No.  Relative therapeutic index                                        ______________________________________                                         12           150                                                               19           164                                                               30           207                                                               ______________________________________                                    

(3) The therapeutic effects of the present compounds, when they were administered orally, were examined using mice infected with Candida albicans ON28.

Candida albicans ON28 was injected in a proportion of 5.7×10⁶ cells/mouse to a group of 10 ICR strain male mice (weight: 19-21 g) intravenously at the tails, whereby the mice were infected with the fungi. Two hours after the infection, a test compound was orally administered in a proportion of 0.1 mg/mouse to the mice, and their survival was observed for 10 days. The relative therapeutic index of the test compound was determined from the average survival days.

The results are shown in Table 2c, in which the relative therapeutic index of each test compound is a value calculated by taking the average survival days Ketoconazole as 100.

                  TABLE 2c                                                         ______________________________________                                         Example No.  Relative therapeutic index                                        ______________________________________                                         10           414                                                               11           423                                                               12           445                                                               19           405                                                               30           414                                                               79           405                                                               80           455                                                               142          405                                                               143          450                                                               145          409                                                               146          418                                                               147          414                                                               ______________________________________                                    

(4) The therapeutic effects of the present compounds, when they were administered orally, were examined using mice infected with Aspergillus fumigatus IFO8868.

Aspergillus fumigatus IFO8868 was injected in a proportion of 5.8×10⁶ cells/mouse to a group of 10 ICR strain male mice (weight: 19-21 g) intravenously at the tails, whereby the mice were infected with the fungi. Two hours after the infection, and continued once daily for six consecutive days, a test compound was orally administered in a proportion of 0.8 mg/mouse to the mice, and their survival was observed for 10 days. The relative therapeutic index of the test compound was determined from the average survival days.

The results are shown in Table 2d, in which the relative therapeutic index of each test compound is a value calculated by taking the average survival days of Ketoconazole as 100.

                  TABLE 2d                                                         ______________________________________                                         Example No.  Relative therapeutic index                                        ______________________________________                                         10           200                                                               11           174                                                               12           237                                                               19           253                                                               30           358                                                               79           400                                                               80           416                                                               142          216                                                               143          242                                                               145          353                                                               146          500                                                               147          526                                                               ______________________________________                                    

3. Acute toxicity

Each of the compounds of Examples 10, 12, 19, 79, 142 and 146 was administered to a group of 5 ICR strain male mice (weight: 29-31 g) intravenously at the tails, and the acute toxicity of each compound was examined.

Each compound was administered in the form of a 50% solution in polyethylene glycol 300.

As a result, the compounds of Example Nos. 12 and 19 gave no dead case when the dose was up to 100 mg/kg, and the compounds of Example Nos. 10, 79, 142 and 146 gave no dead case when the dose was up to 200 mg/kg.

As is clear from the above test results, the present compound exhibits very high pharmacological effects and is highly safe.

The present invention is hereinafter described in more detail referring to Reference Examples and Examples. However, the present invention is not restricted to the Examples.

The carrier used in column chromatography was Silica Gel 60 (manufactured by Merck Co.).

The mixing ratio concerning eluant is by volume in all cases.

In the remarks column of Tables, A and B refer to one of diastereomers and the other, respectively; C refers to a mixture of diastereomers; D refers to a dihydrochloride; E refers to a p-toluenesulfonic acid salt; F refers to an optically active compound; G refers to a monohydrochloride; and H refers to a dioxane adduct.

REFERENCE EXAMPLE 1

In 20 ml of dried tetrahydrofuran was suspended 0.97 g of zinc. To the suspension was dropwise added 3.0 g of ethyl bromodifluoroacetate under reflux. Then, 10 ml of a solution of 2.2 g of 2,2',4'-trichloroacetophenone dissolved in dried tetrahydrofuran was dropwise added under reflux. The resulting mixture was refluxed for 10 minutes. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=1/2) to obtain 1.8 g of oily ethyl 4-chloro-3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxybutyrate.

IR (neat) cm⁻¹ : 3500, 2975, 1755, 1580, 1550

REFERENCE EXAMPLES 2-6

The compounds shown in Table 3 were obtained in the same manner as in Reference Example 1.

In Table 3, R¹, R² and X are those of the following formula:

                  TABLE 3                                                          ______________________________________                                          ##STR23##                                                                     Refer-                                                                         ence                                                                           Example                                                                        No.    R.sup.1      R.sup.2                                                                              X   IR (neat) cm.sup.-1                                                                      Remarks                                ______________________________________                                                 ##STR24##   F     Br  3530, 1760, 1310, 1140                           3                                                                                      ##STR25##   F     Br  3450, 1755, 1370, 1305                           4                                                                                      ##STR26##   F     Cl  3500, 1755, 1610, 1590                           5                                                                                      ##STR27##   H     Cl  3450, 1750, 1605, 1490                                                                   C                                      6                                                                                      ##STR28##   F     Cl  (KBr) 3410, 1745, 1490, 1135                     ______________________________________                                    

REFERENCE EXAMPLE 7

To 40 ml of a solution of lithium diisopropylamide in dried diethyl ether prepared from 4.3 g of diisopropylamine and 26.0 ml of a 1.64N n-hexane solution of n-butyllithium was dropwise added 10 ml of a dried diethyl ether solution containing 5.1 g of ethyl 2-fluoropropionate at -70° to -60° C. The mixture was stirred at the same temperature for 15 minutes. Thereto was dropwise added 60 ml of a dried diethyl ether solution containing 6.2 g of 2-chloro-2',4'-difluoroacetophenone at -70° to -60° C. Then, the temperature of the mixture was elevated to 20° C. in 5 hours. The reaction mixture obtained was introduced into a mixed solvent consisting of 100 ml of ethyl acetate and 50 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=2/1) to obtain 3.9 g of oily ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluoro-2-methylbutyrate (a mixture of diastereomers).

IR (neat) cm⁻¹ : 2985, 1760, 1740, 1505, 1140

REFERENCE EXAMPLE 8

In the column chromatography of Reference Example 7, elution was further conducted with an eluant (n-hexane/toluene=1/1) to obtain 3 g of oily ethyl 4-chloro-3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-2-methylbutyrate (a mixture of diastereomers).

IR (neat) cm⁻¹ : 3490, 1745, 1615, 1300, 1145

REFERENCE EXAMPLE 9

In 150 ml of methylene chloride was dissolved 15.7 g of ethyl 4-chloro-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxybutyrate. To the solution was dropwise added 8.4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene at 5°-10° C. The mixture was subjected to reaction at the same temperature for 2 hours. The resulting reaction mixture was introduced into 150 ml of water and adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=2/1) to obtain 11.1 g of oily ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyrate.

IR (neat) cm⁻¹ : 1770, 1620, 1510, 1145

REFERENCE EXAMPLE 10

Ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutyrate (a mixture of diastereomers) was obtained from ethyl 4-chloro-3-(2,4-difluorophenyl)-2-fluoro-3-hydroxybutyrate (a mixture of diastereomers) in the same manner as in Reference Example 9.

IR (neat) cm⁻¹ : 2980, 1760, 1615, 1505

REFERENCE EXAMPLE 11

In 17 ml of ethanol was dissolved 1.7 g of ethyl 4-chloro-3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxybutyrate. To the resulting solution was added 16.3 ml of a 3N ammonia-ethanol solution. The solution was subjected to reaction at 25°-30° C. for 24 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform) to obtain 0.88 g of 3-(2,4-dichlorophenyl)-3,4-epoxy-2,2-difluorobutanamide.

Melting point: 100.0°-101.0° C.

IR (KBr) cm⁻¹ : 3460, 3280, 3190, 1690, 1610

REFERENCE EXAMPLES 12-14

The compounds shown in Table 4 were obtained in the same manner as in Reference Example 11. In Table 4, R¹, R², R⁷ and R⁸ are those of the following formula:

                  TABLE 4                                                          ______________________________________                                          ##STR29##                                                                     Refer-                                                                         ence                                 IR                                        Example                              (KBr) Re-                                 No.    R.sup.1      R.sup.2                                                                              R.sup.7                                                                               R.sup.8                                                                            cm.sup.-1                                                                            marks                               ______________________________________                                         12                                                                                     ##STR30##   F     H      H   3470, 1705, 1590                          13                                                                                     ##STR31##   F                                                                                     ##STR32##                                                                            H   3270, 1675, 1535                          14                                                                                     ##STR33##   H     H      H   3400, 1660, 1495                                                                     C                                   ______________________________________                                    

REFERENCE EXAMPLE 15

Diastereomers A and B of 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluoro-2-methylbutanamide were obtained from ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2 -fluoro-2-methylbutyrate (a mixture of diastereomers) in the same manner as in Reference Example 11.

IR (KBr) cm⁻¹ :

3455, 1665, 1505, 1265 (diastereomer A)

3385, 1700, 1505, 1150 (diastereomer B)

REFERENCE EXAMPLE 16

4-Bromo-2,2-difluoro-3-hydroxy-3-(thiazol-2-yl)butanamide was obtained from ethyl 4-bromo-2,2-difluoro-3-hydroxy-3-(thiazol-2-yl)butyrate in the same manner as in Reference Example 11.

IR (neat) cm⁻¹ : 3330, 1700, 1405, 1120

REFERENCE EXAMPLE 17

N-cyclopropyl-4-chloro-2,2-difluoro-3-(2-fluorophenyl)-3-hydroxybutanamide was obtained from ethyl 4-chloro-2,2-difluoro-3-(2-fluorophenyl)-3-hydroxybutyrate and cyclopropylamine in the same manner as in Reference Example 11.

IR (KBr) cm⁻¹ : 3355, 1675, 1540, 1485

REFERENCE EXAMPLE 18

In 11 ml of ethanol was dissolved 1.1 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyrate. To the resulting solution was dropwise added 4.7 ml of a 1N aqueous sodium hydroxide solution at 5°-10° C. The solution was subjected to reaction at the same temperature for 10 minutes. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.99 g of oily 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyric acid.

REFERENCE EXAMPLE 19

(1) In 18 ml of dioxane were dissolved 0.9 g of 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyric acid and 0.41 g of N-hydroxysuccinimide. To the resulting solution was added 0.74 g of N,N'-dicyclohexylcarbodiimide. The solution was subjected to reaction at room temperature for 1 hour. The insolubles were removed by filtration.

(2) In a mixed solvent consisting of 14 ml of dioxane and 29 ml of a 1N aqueous sodium hydroxide solution was suspended 1.4 g of 1-(4-chlorophenyl)cyclopropanecarboxamide [this compound can be obtained from 1-(4-chlorophenyl)cyclopropanecarboxylic acid produced according to the method described in Chem. Ber., 119, 3694 (1986)]. To the suspension was dropwise added 4.4 g of a 12% aqueous sodium hypochlorite solution at 5°-10° C. The suspension was subjected to reaction at 20°-25° C. for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. To the thus treated organic layer was added the dioxane solution obtained in (1) above at 20°-25° C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/ethyl acetate =15/1) to obtain 0.37 g of N-[1-(4-chlorophenyl)cyclopropyl]-3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutanamide.

IR (neat) cm⁻¹ : 3325, 1705, 1620, 1600, 1510

REFERENCE EXAMPLE 20

N-(1-methylcyclopropyl)-3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutanamide was obtained in the same manner as in Reference Example 19.

REFERENCE EXAMPLE 21

Ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate was obtained in the same manner as in Reference Example 1, using zinc, ethyl bromodifluoroacetate and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one.

Melting point: 106.5°-108.0° C.

IR (KBr) cm⁻¹ : 3445, 3110, 1765, 1615, 1505

REFERENCE EXAMPLES 22-23

The compounds shown in Table 5 were obtained in the same manner as in Reference Example 21. In Table 5, R¹ and R² are those of the following formula:

                  TABLE 5                                                          ______________________________________                                          ##STR34##                                                                     Refer-                                                                         ence                                                                           Example                                                                        No.       R.sup.1      R.sup.2 IR (KBr) cm.sup.-1                              ______________________________________                                         22                                                                                        ##STR35##   F       3450, 1770, 1605                                23                                                                                        ##STR36##   F        --                                             ______________________________________                                    

REFERENCE EXAMPLE 24

Ethyl 2-benzyl-3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate (a mixture of diastereomers) was obtained in the same manner as in Reference Example 7, using ethyl 2-fluoro-3-phenylpropionate and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one.

IR (neat) cm⁻¹ : 3385, 1740, 1500, 1275

REFERENCE EXAMPLE 25

Ethyl 2-fluoropropionate and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one were treated in the same manner as in Reference Example 7, and the residue thus obtained was purified by a column chromatography (eluant: ethyl acetate/toluene=1/4) to obtain ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).

IR (KBr) cm⁻¹ : 3460, 1740, 1615, 1500

REFERENCE EXAMPLE 26

A mixture of 2.4 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutyrate (a mixture of diastereomers) and 6.4 g of 1,2,4-triazole was subjected to reaction at 90°-100° C. for 8 hours. To the reaction mixture were then added 10 ml of ethyl acetate and 5 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 650 mg of ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).

IR (KBr) cm⁻¹ : 3140, 1760, 1620, 1210, 1100

Elution was further continued to obtain 170 mg of the other of the diastereomers.

IR (KBr) cm⁻¹ : 3135, 1755, 1505, 1220, 1130

REFERENCE EXAMPLES 27-38

The compounds shown in Table 6 were obtained in the same manner as in Reference Example 1.

In Table 6, R¹ and X are those of the following formula:

                  TABLE 6                                                          ______________________________________                                          ##STR37##                                                                     Refer-                                                                         ence                                                                           Example                                                                        No.     R.sup.1        X      IR (neat) cm.sup.-1                              ______________________________________                                         27                                                                                      ##STR38##     Cl     3510, 1760, 1315, 1095                           28                                                                                      ##STR39##     Cl     3615, 1765, 1470, 1110                           29                                                                                      ##STR40##     Cl      --                                              30                                                                                      ##STR41##     Cl     3495, 1760, 1315, 1080                           31                                                                                      ##STR42##     Cl     3540, 1765, 1450, 1150                           32                                                                                      ##STR43##     Cl     3620, 1765, 1600, 1125                           33                                                                                      ##STR44##     Cl     3460, 1760, 1515, 1420                           34                                                                                      ##STR45##     Cl     3490, 1760, 1515, 1475                           35                                                                                      ##STR46##     Cl     3420, 1750, 1500, 1180                           36                                                                                      ##STR47##     Cl     3495, 1765, 1425, 1335                           37                                                                                      ##STR48##     Cl     3505, 1760, 1485, 1315                           38                                                                                      ##STR49##     Cl     3505, 1760, 1510, 1165                           ______________________________________                                    

REFERENCE EXAMPLE 39

Ethyl 3,4-epoxy-2,2-difluoro-3-(2-methoxyphenyl)butyrate was obtained from 2-bromo-2'-methoxyacetophenone in the same manner as in Reference Example 1.

IR (neat) cm⁻¹ : 1770, 1605, 1310, 1020

REFERENCE EXAMPLES 40-52

The compounds shown in Table 7 were obtained in the same manner as in Reference Example 21.

In Table 7, R¹ is that of the following formula:

                  TABLE 7                                                          ______________________________________                                          ##STR50##                                                                     Reference                                                                      Example                                                                        No.       R.sup.1        IR (KBr) cm.sup.-1                                    ______________________________________                                         40                                                                                        ##STR51##     3130, 1765, 1520, 1140                                41                                                                                        ##STR52##     3070, 1765, 1515, 1315                                42                                                                                        ##STR53##     3170, 1770, 1305, 1140                                43                                                                                        ##STR54##     3120, 1755, 1495, 1315                                44                                                                                        ##STR55##     3130, 1765, 1330, 1130                                45                                                                                        ##STR56##     (neat) 3135, 1765, 1315, 1135                         46                                                                                        ##STR57##     (neat) 3355, 1770, 1605, 1315                         47                                                                                        ##STR58##     (neat) 3135, 1765, 1310, 1100                         48                                                                                        ##STR59##     (neat) 3130, 1760, 1510, 1140                         49                                                                                        ##STR60##     (neat) 3135, 1765, 1515, 1100                         50                                                                                        ##STR61##     (neat) 3405, 1765, 1310, 1100                         51                                                                                        ##STR62##     (neat) 3125, 1765, 1530, 1350                         52                                                                                        ##STR63##     (neat) 1765, 1515                                     ______________________________________                                    

EXAMPLE 1

In 8 ml of N,N-dimethylformamide was dissolved 0.8 g of 3-(2,4-dichlorophenyl)-3,4-epoxy-2,2-difluorobutanamide. To the resulting solution were added 0.59 g of anhydrous potassium carbonate and 0.29 g of 1,2,4-triazole. The mixture was subjected to reaction at 80°-90° C. for 1 hour. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 10 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 1.0 with 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=100/1) to obtain 0.40 g of 3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.

Melting point: 194.0°-195.5° C.

IR (KBr) cm⁻¹ : 3310, 3110, 1700, 1580, 1500

EXAMPLES 2-6

The compounds shown in Table 8 were obtained in the same manner as in Example 1. In Table 8, R¹, R², R⁷ and R⁸ are those of the following formula:

                                      TABLE 8                                      __________________________________________________________________________      ##STR64##                                                                     Example                         Melting Point                                  No.  R.sup.1  R.sup.2                                                                            R.sup.7     R.sup.8                                                                          (°C.)                                                                          IR (KBr) cm.sup.-1                                                                        Remarks                      __________________________________________________________________________           ##STR65##                                                                              F   H           H Amorphous                                                                             3500, 1710, 1505, 1420                  3                                                                                    ##STR66##                                                                              F                                                                                   ##STR67##  H 112.0-114.0                                                                           3275, 1670, 1505, 1425                  4                                                                                    ##STR68##                                                                              F                                                                                   ##STR69##  H 124.5-125.5                                                                           3325, 1675, 1615, 1540                  5                                                                                    ##STR70##                                                                              F                                                                                   ##STR71##  H Amorphous                                                                             3410, 1700, 1615, 1500                  6                                                                                    ##STR72##                                                                              CH.sub.3                                                                           H           H 120.5-121.0 134.0-136.0                                                               3490, 1675, 1500, 1420 3445, 1675,                                             1500, 1275 A B                          __________________________________________________________________________

EXAMPLE 7

2,2-Difluoro-3-hydroxy-3-(thiazol-2-yl)-4-(1H-1,2,4-triazol-1-yl)butanamide was obtained from 4-bromo-2,2-difluoro-3-hydroxy-3-(thiazol-2-yl)butanamide in the same manner as in Example 1.

Melting point: 173.0°-175.0° C.

IR (KBr) cm⁻¹ : 3260, 1715, 1515, 1180, 1105

EXAMPLE 8

N-cyclopropyl-2,2-difluoro-3-(2-fluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide was obtained from N-cyclopropyl-4-chloro-2,2-difluoro-3-(2-fluorophenyl)-3-hydroxybutanamide in the same manner as in Example 1.

Melting point: 134.5°-135.0° C.

IR (KBr) cm⁻¹ : 3395, 3160, 1695, 1520

EXAMPLE 9

3- (2,4-Difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide (one of the diastereomers) was obtained from 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutanamide (a mixture of diastereomers) in the same manner as in Reference Example 26.

Melting point: 185.5°-188.5° C.

IR (KBr) cm⁻¹ : 3230, 1690, 1615, 1500, 1140

EXAMPLE 10

In 30 ml of ethanol was dissolved 3.0 g of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 6 ml of concentrated aqueous ammonia. The resulting mixture was subjected to reaction at 20°-25° C. for 5 hours. Then, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 2.1 g of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.

Melting point: 164.5°-165.0° C.

IR (KBr) cm⁻¹ : 3300, 1690, 1610, 1435, 1270

EXAMPLES 11-38

The compounds shown in Table 9 were obtained in the same manner as in Example 10. In Table 9, R¹, R², R⁷ and R⁸ are those of the following formula:

                                      TABLE 9                                      __________________________________________________________________________      ##STR73##                                                                     Example                          Melting Point                                 No.  R.sup.1  R.sup.2                                                                            R.sup.7                                                                          R.sup.8      (°C.)                                                                          IR (KBr) cm.sup.-1                                                                        Remarks                     __________________________________________________________________________     11                                                                                   ##STR74##                                                                              F   H CH.sub.3     165.5-166.5                                                                           3350, 1685, 1495, 1275                 12                                                                                   ##STR75##                                                                              F   H CH.sub.2 CH.sub.3                                                                           125.0-125.5                                                                           3330, 1690, 1505, 1105                 13                                                                                   ##STR76##                                                                              F   H CH.sub.2 CF.sub.3                                                                           129.0-129.5                                                                           3345, 1710, 1620, 1540                 14                                                                                   ##STR77##                                                                              F   H CH.sub.2 CH.sub.2 OH                                                                        101.0-103.0                                                                           3300, 1680, 1505, 1270                 15                                                                                   ##STR78##                                                                              F   H                                                                                 ##STR79##   247.0-249.0 (decomp.)                                                                 3265, 2695, 1705,                                                                         D545                        16                                                                                   ##STR80##                                                                              F   H CH.sub.2 CH.sub.2 CH.sub.3                                                                  100.5-101.5                                                                           3330, 1695, 1615, 1540                 17                                                                                   ##STR81##                                                                              F   H CH.sub.2 CHCH.sub.2                                                                         123.5-124.0                                                                           3330, 1685, 1540, 1420                 18                                                                                   ##STR82##                                                                              F   H CH.sub.2 CCH 92.0-94.0                                                                             3305, 1695, 1615, 1505                 19                                                                                   ##STR83##                                                                              F   H                                                                                 ##STR84##   156.0-157.0                                                                           3315, 1675, 1505, 1275                 20                                                                                   ##STR85##                                                                              F   H                                                                                 ##STR86##   132.5-133.0                                                                           3325, 1685, 1505, 1425                 21                                                                                   ##STR87##                                                                              F   H                                                                                 ##STR88##   145.5-146.5                                                                           3230, 1675, 1500, 1135                 22                                                                                   ##STR89##                                                                              F   H                                                                                 ##STR90##   107.0-108.0                                                                           3360, 1700, 1500, 1425                 23                                                                                   ##STR91##                                                                              F   H                                                                                 ##STR92##   Oily   (neat) 3355, 1740, 1700, 1615          24                                                                                   ##STR93##                                                                              F   (CH.sub.2 ) .sub.4                                                                            144.0-144.5                                                                           3070, 1640, 1495, 1440                 25                                                                                   ##STR94##                                                                              F                                                                                   ##STR95##     Amorphous                                                                             (neat) 3125, 1655, 1450, 1275          26                                                                                   ##STR96##                                                                              F   H NH.sub.2     194.0-195.0                                                                           3150, 1690, 1625, 1610                 27                                                                                   ##STR97##                                                                              F   H OH           175.0-176.0 (decomp.)                                                                 3150, 1670, 1610, 1590                 28                                                                                   ##STR98##                                                                              H   H                                                                                 ##STR99##   160.5-161.5 90.5-91.0                                                                 3240, 1675, 1505, 1275 3290,                                                   1650, 1505, 1275                                                                          A B                         29                                                                                   ##STR100##                                                                             CH.sub.3                                                                           H                                                                                 ##STR101##  165.0-166.0                                                                           3320, 1640, 1550,                                                                         A505                        30                                                                                   ##STR102##                                                                             F   H                                                                                 ##STR103##  109.5-110.5                                                                           3270, 1685, 1605, 1510                 31                                                                                   ##STR104##                                                                             F   H H             --    3350, 1720, 1365, 1110                 32                                                                                   ##STR105##                                                                             F   H CH.sub.2 CH.sub.2 OCH.sub.3                                                                 83.0-84.0                                                                             3335, 1695, 1545, 1500                 33                                                                                   ##STR106##                                                                             F   H                                                                                 ##STR107##  122.5-123.0                                                                           3345, 1685, 1620, 1505                 34                                                                                   ##STR108##                                                                             F   H CH.sub.2 CH.sub.2 CN                                                                        123.0-124.0                                                                           3330, 2265, 1705, 1515                 35                                                                                   ##STR109##                                                                             F   H                                                                                 ##STR110##  101.0-101.5                                                                           3240, 1680, 1505, 1110                 36                                                                                   ##STR111##                                                                             F   H CH.sub.2 CH.sub.2 SH                                                                        105.5-107.0                                                                           3315, 1685, 1505, 1135                 37                                                                                   ##STR112##                                                                             F   H CH.sub.2 CH.sub.2 SCH.sub.3                                                                  --    3345, 1690, 1505, 1105                 38                                                                                   ##STR113##                                                                             F   H CH.sub.2 CH.sub.2 CH.sub.2 CN                                                               135.0-135.5                                                                           3480, 2245, 1680,                      __________________________________________________________________________                                             1505                              

EXAMPLE 39

In 1 ml of ethanol was dissolved 100 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 330 mg of 2,6-dimethylmorpholine. The resulting mixture was subjected to reaction for 2 hours under reflux. Then, the reaction mixture was introduced into a mixed solvent consisting of 20 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform) to obtain 10 mg of 4-[3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanoyl]-2,6-dimethylmorpholine.

IR (KBr) cm⁻¹ : 3445, 1660, 1505, 1275, 1085

EXAMPLES 40-41

The compounds shown in Table 10 were obtained in the same manner as in Example 39. In Table 10, R¹, R², R⁷ and R⁸ are those of the following formula:

                                      TABLE 10                                     __________________________________________________________________________      ##STR114##                                                                    Example                  Melting Point                                         No.  R.sup.1  R.sup.2                                                                          R.sup.7                                                                            R.sup.8                                                                             (°C.)                                                                          IR (KBr) cm.sup.-1                             __________________________________________________________________________     40                                                                                   ##STR115##                                                                             F CH.sub.3                                                                           CH.sub.3                                                                            85.5-86.5                                                                             3050, 1655, 1495, 1270                         41                                                                                   ##STR116##                                                                             F H   OCH.sub.3                                                                           139.5-140.5                                                                           3455, 1705, 1620, 1140                         __________________________________________________________________________

EXAMPLE 42

A mixture of 100 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate and 370 mg of 4-chloroaniline was subjected to reaction at 150°-160° C. for 5 hours. The reaction mixture was cooled to room temperature. Thereto were added 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 30 mg of N-(4-chlorophenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.

Melting point: 86.0°-87.0° C.

IR (KBr) cm⁻¹ : 3400, 1720, 1590, 1490, 1140

EXAMPLES 43-46

The compounds shown in Table 11 were obtained in the same manner as in Example 42. In Table 11, R¹, R², R⁷ and R⁸ are those of the following formula:

                                      TABLE 11                                     __________________________________________________________________________      ##STR117##                                                                    Example                     Melting Point                                      No.  R.sup.1  R.sup.2                                                                          R.sup.7                                                                          R.sup.8   (°C.)                                                                          IR (KBr) cm.sup.-1                                                                        Remarks                          __________________________________________________________________________     43                                                                                   ##STR118##                                                                             F H                                                                                 ##STR119##                                                                              187.0-188.0                                                                           3400, 1700, 1610, 1500                                                                    E                                44                                                                                   ##STR120##                                                                             F H                                                                                 ##STR121##                                                                               --    3405, 1710, 1620, 1505                      45                                                                                   ##STR122##                                                                             F H                                                                                 ##STR123##                                                                              131.5-132.5                                                                           3400, 1700, 1595, 1530                      46                                                                                   ##STR124##                                                                             F H                                                                                 ##STR125##                                                                              134.0-138.0                                                                           3100, 1720, 1580, 1265                      __________________________________________________________________________

EXAMPLE 47

In 2 ml of ethanol was dissolved 160 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 2 ml of a 1N aqueous sodium hydroxide solution at 0°-5° C. The mixture was subjected to reaction at the same temperature for 10 minutes. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained, and the resulting crystals were collected by filtration to obtain 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid.

Melting point: 187°-200° C. (decomp.)

IR (KBr) cm⁻¹ : 3450, 1760, 1610, 1495, 1205

EXAMPLES 48-49

The compounds shown in Table 12 were obtained in the same manner as in Example 47. In Table 12, R¹, R² and R³ are those of the following formula:

                                      TABLE 12                                     __________________________________________________________________________      ##STR126##                                                                    Example                          Melting Point                                 No.  R.sup.1  R.sup.2   R.sup.3  (°C.)                                                                          IR (KBr) cm.sup.-1                                                                        Remarks                     __________________________________________________________________________     48                                                                                   ##STR127##                                                                             F                                                                                         ##STR128##                                                                             --     3405, 1700, 1505, 1135                 49                                                                                   ##STR129##                                                                              ##STR130##                                                                              COOH     -- --  3420, 1615, 1500, 1420 3120,                                                   1615, 1500, 1455                                                                          A B                         __________________________________________________________________________

EXAMPLE 50

In 20 ml of dioxane were dissolved 300 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid and 110 mg of N-hydroxysuccinimide. To the resulting solution was added 200 mg of N,N'-dicyclohexylcarbodiimide. Then, the resulting mixture was subjected to reaction at 15°-25° C. for 3 hours. The reaction mixture was subjected to filtration to remove the insolubles, and 4.5 ml of a concentrated aqueous ammonia solution was added to the filtrate. The resulting mixture was subjected to reaction at 15°-25° C. for 20 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 10 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=10/1) to obtain 70 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.

Melting point: 164.5°-165.0° C.

IR (KBr) cm⁻¹ : 3300, 1690, 1610, 1435, 1270

EXAMPLES 51-56

The compounds shown in Table 13 were obtained in the same manner as in Example 50. In Table 13, R¹, R², R⁷ and R⁸ are those of the following formula:

                                      TABLE 13                                     __________________________________________________________________________      ##STR131##                                                                    Example                                 Melting Point                          No.  R.sup.1  R.sup.2   R.sup.7                                                                              R.sup.8   (°C.)                                                                          IR (KBr)                                                                                  Remarks-1            __________________________________________________________________________     51                                                                                   ##STR132##                                                                             F                                                                                         ##STR133##                                                                          H         144.5-145.5                                                                           3440, 1715, 1615, 1530          52                                                                                   ##STR134##                                                                             F         H                                                                                     ##STR135##                                                                              108.0-109.5 (decomp.)                                                                 3370, 2230, 1730, 1530          53                                                                                   ##STR136##                                                                             F         H                                                                                     ##STR137##                                                                              117.0-120.0 (decomp.)                                                                 3355, 1700, 1540, 1440          54                                                                                   ##STR138##                                                                             F         H                                                                                     ##STR139##                                                                              119.0-121.0 (decomp.)                                                                 3385, 1705, 1615, 1500          55                                                                                   ##STR140##                                                                             F         H                                                                                     ##STR141##                                                                              112.0-115.0 (decomp.)                                                                 3315, 1700, 1665, 1505          56                                                                                   ##STR142##                                                                              ##STR143##                                                                              H     H         121.5-124.0 204.5-205.5                                                               3495, 1685, 1500, 1270                                                         3470, 1680, 1500,                                                                         A B5                 __________________________________________________________________________

EXAMPLE 57

In 7 ml of dichloromethane was suspended 0.33 g of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrohydrazide. To the suspension was added 0.12 g of triethylamine. Thereto was dropwise added 0.19 g of 4-fluorobenzoyl chloride at 5°-10° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of dichloromethane and 10 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform) to obtain 0.25 g of N'-(4-fluorobenzoyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrohydrazide.

Melting point: 127.0°-130.0° C.

IR (KBr) cm⁻¹ : 3330, 1730, 1705, 1590, 1495

EXAMPLE 58

In 4 ml of methylene chloride was dissolved 80 mg of N-(2-methoxyphenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. To the resulting solution were added 120 mg of ethanethiol and 130 mg of aluminum chloride at -5° to 0° C. The resulting mixture was subjected to reaction at 20°-25° C. for 20 hours. Then, the reaction mixture was introduced into a mixed solvent consisting of 10 ml of chloroform and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 30 mg of N-(2-hydroxyphenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.

Melting point: 121.0°-126.0° C.

IR (KBr) cm⁻¹ : 3420, 1690, 1540, 1455, 1270

EXAMPLE 59

In 5 ml of pyridine was dissolved 150 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. To the solution was added 100 mg of trichloroacetyl chloride at 0°-5° C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. Then, the reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=50/1) to obtain 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile.

Melting point: 130.5°-131.5° C.

IR (KBr) cm⁻¹ : 3120, 2250, 1605, 1420, 1115

EXAMPLES 60-61

The compounds shown in Table 14 were obtained in the same manner as in Example 59. In Table 14, R¹, R² and R³ are those of the following formula:

                                      TABLE 14                                     __________________________________________________________________________      ##STR144##                                                                    Example               Melting Point                                            No.  R.sup.1  R.sup.2                                                                            R.sup.3                                                                            (°C.)                                                                          IR (KBr) cm.sup.-1                                                                        Remarks                                __________________________________________________________________________     60                                                                                   ##STR145##                                                                             H   CN  144.5-145.0                                                                           3100, 1615, 1495, 1270                                                                    A                                      61                                                                                   ##STR146##                                                                             CH.sub.3                                                                           CN   --    3445, 1610, 1505, 1090                                                                    A                                      __________________________________________________________________________

EXAMPLE 62

To 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile were added 0.2 ml of diethyl dithiophosphate and 0.04 ml of water. The resulting mixture was subjected to reaction at 80°-90° C. for 5 hours. The reaction mixture was purified by a column chromatography (eluant: chloroform/methanol=50/1) to obtain an oily matter. To the oily matter was added 0.5 ml of a 2N hydrochloric acid-dioxane solution, and then diethyl ether was added. The resulting crystals were collected by filtration to obtain 110 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanethioamide hydrochloride.

Melting point: 178° C. (decomp.)

IR (KBr) cm⁻¹ : 3420, 1625, 1505, 1425, 1140

EXAMPLE 63

In 6 ml of chloroform was dissolved 300 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile. To the resulting solution were added 83 mg of hydroxylamine hydrochloride and 100 mg of triethylamine at 0°-5° C. The resulting mixture was subjected to reaction at 20°-25° C. for 3 hours. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of chloroform and 5 ml of water. The resulting solution was adjusted to pH 9.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 330 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide oxime.

IR (KBr) cm⁻¹ : 3340, 1665, 1490, 1265, 1135

EXAMPLE 64

3-(2,4-Difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide O-methyloxime was obtained in the same manner as in Example 63.

Melting point: 113.5°-114.5° C.

IR (KBr) cm⁻¹ : 3365, 1645, 1505, 1275, 1105

EXAMPLE 65

In 2 ml of methanol was dissolved 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile. The solution was refluxed for 6 hours. Then, the solvent was removed by distillation under reduced pressure, and diisopropyl ether was added to the residue obtained. The resulting crystals were collected by filtration to obtain 90 mg of methyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butylimidate.

Melting point: 115.5°-116.5° C.

IR (KBr) cm⁻¹ : 3300, 1670, 1610, 1495, 1115

EXAMPLE 66

In 1 ml of chloroform was dissolved 90 mg of methyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butylimidate. To the solution was added 90 mg of cyclopropylamine. The resulting mixture was refluxed for 3 hours. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain an oily matter. To the oily matter was added 0.5 ml of a 2N hydrochloric acid-dioxane solution, and acetone was then added. The resulting crystals were collected by filtration to obtain 20 mg of N-cyclopropyl-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-butanamidine dihydrochloride.

Melting point: 229.5°-230.5° C.

IR (KBr) cm⁻¹ : 3300, 1665, 1605, 1495, 1270

EXAMPLE 67

In 4 ml of a 6N ammonia-methanol solution was dissolved 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile. The solution was subjected to reaction at 70° C. for 7 hours in a sealed tube. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=10/1). To the purified residue was added 0.5 ml of a 2N hydrochloric acid-dioxane solution, and dioxane was thereafter added. The resulting crystals were collected by filtration to obtain 50 mg of a dioxane adduct of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-dihydrochloride.

Melting point: 109.5°-110.5° C.

IR (KBr) cm-¹ : 3420, 1715, 1620, 1505, 1150

EXAMPLE 68

In 5 ml of ethanol was dissolved 1.0 g of ethyl 4-chloro-2,2-difluoro-3-hydroxy-3-phenylbutyrate. To the resulting solution was added 0.98 ml of a concentrated aqueous ammonia. The solution was subjected to reaction at 25°30° C. for 3 hours. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 10 ml of N,N-dimethylformamide. To the solution were added 0.5 g of 1,2,4-triazole and 1.0 g of anhydrous potassium carbonate. The resulting mixture was subjected to reaction at 70° C. for 10 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant:chloroform/methanol=50/1) to obtain 0.30 g of 2,2-difluoro-3-hydroxy-3-phenyl-4-(1H-1,2,4-triazol-1-yl)butanamide.

Melting point: 160.5°-161.0° C.

IR (KBr) cm⁻ 1: 3325, 1700, 1510, 1185

EXAMPLES 69-102

The compounds shown in Table 15 were obtained in the same manner as in Example 68. In Table 15, R¹, R⁷ and R⁸ are those of the following formula:

                                      TABLE 15                                     __________________________________________________________________________      ##STR147##                                                                    Example                 Melting Point                                          No.  R.sup.1    R.sup.7                                                                              R.sup.8                                                                          (°C.)                                                                          IR (KBr) cm.sup.-1                              __________________________________________________________________________     69                                                                                   ##STR148##                                                                               CH.sub.2 CH.sub.3                                                                    H 160.0-161.5                                                                           3275, 1690, 1510, 1105                          70                                                                                   ##STR149##                                                                                ##STR150##                                                                          H 96.5-97.0                                                                             3290, 1695, 1510, 1110                          71                                                                                   ##STR151##                                                                               H     H 168.0-169.0                                                                           3165, 1675, 1215, 1115                          72                                                                                   ##STR152##                                                                               CH.sub.3                                                                             H 151.5-152.5                                                                           3315, 1685, 1220, 1110                          73                                                                                   ##STR153##                                                                               CH.sub.2 CH.sub.3                                                                    H 122.5-123.5                                                                           3275, 1675, 1515, 1140                          74                                                                                   ##STR154##                                                                               CH.sub.3                                                                             H 147.5-148.0                                                                           3325, 1685, 1510, 1135                          75                                                                                   ##STR155##                                                                               CH.sub.2 CH.sub.3                                                                    H 107.0-108.0                                                                           3275, 1675, 1510, 1135                          76                                                                                   ##STR156##                                                                               H     H 164.5-165.0                                                                           3395, 1730, 1620, 1140                          77                                                                                   ##STR157##                                                                               CH.sub.2 CH.sub.3                                                                    H 114.0-114.5                                                                           3480, 1680, 1625, 1140                          78                                                                                   ##STR158##                                                                                ##STR159##                                                                          H 145.5-146.0                                                                           3475, 1675, 1625, 1135                          79                                                                                   ##STR160##                                                                               H     H 133.0-134.0                                                                           3320, 1710, 1600, 1580                          80                                                                                   ##STR161##                                                                               CH.sub.3                                                                             H 143.5-144.5                                                                           3340, 1685, 1600, 1145                          81                                                                                   ##STR162##                                                                               CH.sub.2 CH.sub.3                                                                    H 105.0-106.0                                                                           3345, 1680, 1510, 1145                          82                                                                                   ##STR163##                                                                               H     H 181.5-183.0                                                                           3315, 1705, 1615, 1180                          83                                                                                   ##STR164##                                                                               CH.sub.2 CH.sub.3                                                                    H 128.5-129.5                                                                           3260, 1675, 1515, 1120                          84                                                                                   ##STR165##                                                                               H     H 195.0-196.0                                                                           3515, 1720, 1435, 1135                          85                                                                                   ##STR166##                                                                                ##STR167##                                                                          H 137.5-138.5                                                                           3245, 1685, 1510, 1025                          86                                                                                   ##STR168##                                                                               H     H 148.0-149.0                                                                           3485, 1715, 1600, 1125                          87                                                                                   ##STR169##                                                                               H     H 155.5-156.5                                                                           3325, 1700, 1515, 1105                          88                                                                                   ##STR170##                                                                               CH.sub.2 CH.sub.3                                                                    H 147.0-148.0                                                                           3445, 1710, 1515, 1120                          89                                                                                   ##STR171##                                                                                ##STR172##                                                                          H 165.0-166.0                                                                           3450, 1710, 1515, 1120                          90                                                                                   ##STR173##                                                                               H     H 227.5-228.0                                                                           3440, 1715, 1515, 1475                          91                                                                                   ##STR174##                                                                               CH.sub.2 CH.sub.3                                                                    H 97.5-99.0                                                                             3275, 1690, 1515, 1140                          92                                                                                   ##STR175##                                                                                ##STR176##                                                                          H 118.5-119.5                                                                           3220, 1675, 1510, 1115                          93                                                                                   ##STR177##                                                                               H     H 137.5-139.0                                                                           3245, 1705, 1500, 1110                          94                                                                                   ##STR178##                                                                               CH.sub.2 CH.sub.3                                                                    H 142.5-143.0                                                                           3445, 1710, 1495, 1125                          95                                                                                   ##STR179##                                                                                ##STR180##                                                                          H 150.5-151.5                                                                           3455, 1710, 1495, 1125                          96                                                                                   ##STR181##                                                                               H     H 147.5-148.5                                                                           3485, 1700, 1425, 1335                          97                                                                                   ##STR182##                                                                               CH.sub.2 CH.sub.3                                                                    H 128.0-129.0                                                                           3280, 1680, 1425, 1335                          98                                                                                   ##STR183##                                                                                ##STR184##                                                                          H 159.5-160.5                                                                           3315, 1675, 1335, 1135                          99                                                                                   ##STR185##                                                                               H     H 123.0-124.0                                                                           3300, 1700, 1510, 1285                          100                                                                                  ##STR186##                                                                               CH.sub.2 CH.sub.3                                                                    H 105.0-105.5                                                                           3290, 1675, 1510, 1140                          101                                                                                  ##STR187##                                                                               H     H 128.0-128.5                                                                           3335, 1700, 1515, 1255                          102                                                                                  ##STR188##                                                                               H     H 134.5-135.0                                                                           3165, 1715, 1490, 1125                          __________________________________________________________________________

EXAMPLES 103-129

The compounds shown in Table 16 were obtained in the same manner as in Example 10. In Table 16, R¹, R⁷ and R⁸ are those of the following formula:

                                      TABLE 16                                     __________________________________________________________________________      ##STR189##                                                                    Example                    Melting Point                                       No.  R.sup.1   R.sup.7   R.sup.8                                                                          (°C.)                                                                          IR (KBr) cm.sup.-1                                                                        Remarks                           __________________________________________________________________________     103                                                                                  ##STR190##                                                                              H         H 182.0-183.0                                                                           3320, 1700, 1515, 1085                       104                                                                                  ##STR191##                                                                              CH.sub.2 CH.sub.3                                                                        H 173.0-173.5                                                                           3265, 1685, 1515, 1095                       105                                                                                  ##STR192##                                                                               ##STR193##                                                                              H 125.0-126.0                                                                           3430, 1700, 1520, 1135                       106                                                                                  ##STR194##                                                                              H         H 180.5-181.5                                                                           3300, 1700, 1180, 1090                       107                                                                                  ##STR195##                                                                              CH.sub.2 CH.sub.3                                                                        H 122.0-122.5                                                                           3280, 1695, 1510, 1095                       108                                                                                  ##STR196##                                                                               ##STR197##                                                                              H 129.0-130.0                                                                           3380, 1690, 1510, 1120                       109                                                                                  ##STR198##                                                                              H         H 154.5-155.5                                                                           3460, 1700, 1505, 1430                       110                                                                                  ##STR199##                                                                              CH.sub.2 CH.sub.3                                                                        H 106.5-108.0                                                                           3275, 1695, 1510, 1110                       111                                                                                  ##STR200##                                                                              CH.sub.2 CH.sub.2 F                                                                      H 114.0-114.5                                                                           3450, 1710, 1620, 1130                       112                                                                                  ##STR201##                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                             H 111.0-112.0                                                                           3335, 1680, 1505, 1110                       113                                                                                  ##STR202##                                                                               ##STR203##                                                                              H 96.0-96.5                                                                             3445, 1705, 1530, 1115                       114                                                                                  ##STR204##                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                      H --     3330, 1695, 1540, 1505                       115                                                                                  ##STR205##                                                                               ##STR206##                                                                              H --     3435, 1685, 1505, 1140                       116                                                                                  ##STR207##                                                                              H         H 169.5-171.5                                                                           3310, 1700, 1495, 1435                       117                                                                                  ##STR208##                                                                              CH.sub.2 CH.sub.3                                                                        H 113.5-114.5                                                                           3300, 1685, 1490, 1170                       118                                                                                  ##STR209##                                                                               ##STR210##                                                                              H 134.5-135.5                                                                           3335, 1675, 1495, 1110                       119                                                                                  ##STR211##                                                                              H         H 147.0-148.0                                                                           3425, 1700, 1330, 1130                       120                                                                                  ##STR212##                                                                              CH.sub.2 CH.sub.3                                                                        H 139.0-140.0                                                                           3280, 1700, 1510, 1330                       121                                                                                  ##STR213##                                                                               ##STR214##                                                                              H 142.5-143.5                                                                           3390, 1690, 1510, 1335                       122                                                                                  ##STR215##                                                                              H         H 185.0-186.0                                                                           3320, 1700, 1510, 1095                       123                                                                                  ##STR216##                                                                              H         H 148.5-150.5                                                                           3320, 1705, 1510, 1175                       124                                                                                  ##STR217##                                                                              H         H 176.0-176.5                                                                           3475, 1705, 1515, 1090                       125                                                                                  ##STR218##                                                                              H         H 182.5-183.5                                                                           3360, 1700, 1510, 1090                       126                                                                                  ##STR219##                                                                              H         H 123.5-124.0                                                                           3270, 1715, 1515, 1095                       127                                                                                  ##STR220##                                                                              H         H 182.5-183.0                                                                           3450, 2235, 1720, 1095                       128                                                                                  ##STR221##                                                                              H         H 238.5-242.0                                                                           3445, 1715, 1520, 1355                       129                                                                                  ##STR222##                                                                              H         H --     3395, 1710, 1600, 1560                                                                    G                                 __________________________________________________________________________

EXAMPLES 130-132

The compounds shown in Table 17 were obtained in the same manner as in Example 39.

In Examples 131 and 132, the separation of diastereomers into individual components can be conducted by a column chromatography (eluant: toluene/ethyl acetate=3/1).

In Table 17, R¹ and R⁴ are those of the following formula:

                                      TABLE 17                                     __________________________________________________________________________      ##STR223##                                                                    Example                      Melting                                           No.  R.sup.1  R.sup.4        Point (°C.)                                                                   IR (KBr) cm.sup.-1                                                                        Remarks                          __________________________________________________________________________     130                                                                                  ##STR224##                                                                              ##STR225##    137.0-138.0                                                                          3405, 1655, 1135, 1115                      131                                                                                  ##STR226##                                                                              ##STR227##    Amorphous Amorphous                                                                  3315, 1650, 1445, 1135 3315, 1655,                                             1445, 1135 A B                              132                                                                                  ##STR228##                                                                              ##STR229##    Amorphous Amorphous                                                                  3310, 1650, 1505, 1140 3315, 1650,                                             1500, 1140 A B                              __________________________________________________________________________

EXAMPLE 133

To 4 ml of 47% hydrobromic acid was added 500 mg of N-(4-chlorobenzyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. The resulting mixture was refluxed for 6 hours. Thereto were added 20 ml of toluene and 20 ml of water. The resulting solution was adjusted to pH 8.5 with sodium carbonate. The aqueous layer was separated and 20 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 230 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid.

Melting point: 187°-200° C. (decomp.)

IR (KBr) cm⁻¹ : 3450, 1760, 1610, 1495, 1205

EXAMPLES 134-135

The compounds shown in Table 18 were obtained in the same manner as in Example 133, using the diastereomers A obtained in Example 131 and Example 132.

In Table 18, R¹ is that of the following formula:

                                      TABLE 18                                     __________________________________________________________________________      ##STR230##                                                                    Example       Melting                                                          No.  R.sup.1  Point (°C.)                                                                   IR (KBr) cm.sup.-1                                                                        [α].sub.D.sup.25                                                                  Remarks                                __________________________________________________________________________     134                                                                                  ##STR231##                                                                             Amorphous                                                                            3145, 1735, 1505, 1145                                                                    --       F                                      135                                                                                  ##STR232##                                                                             102.5-104.5                                                                          3235, 1760, 1600, 1485                                                                    -30.7° (C = 1.00,                                                                FHOH)                                  __________________________________________________________________________

EXAMPLES 136-148

The compounds shown in Table 19 were obtained in the same manner as in Example 50.

The optically active compounds of Examples 142-148 were produced from the compounds obtained in Examples 134-135.

In Table 19, R¹, R⁷ and R⁸ are those of the following formula:

                                      TABLE 19                                     __________________________________________________________________________      ##STR233##                                                                    Example                       Melting                                          No.  R.sup.1   R.sup.7     R.sup.8                                                                           Point (°C.)                                                                   IR (KBr) cm.sup.-1                                                                         [α].sub.D.sup.25                                                                   Remarks              __________________________________________________________________________     136                                                                                  ##STR234##                                                                               ##STR235## H  158.0-159.0                                                                          3365, 1690, 1325, 1065                                                                     --                             137                                                                                  ##STR236##                                                                               ##STR237## H  176.5-177.0                                                                          3360, 2230, 1720, 1555                                                                     --                             138                                                                                  ##STR238##                                                                               ##STR239## H  154.0-154.5                                                                          3290, 2265, 1700, 1100                                                                     --                             139                                                                                  ##STR240##                                                                               ##STR241## H  125.5-126.0                                                                          3445, 1680, 1510, 1130                                                                     --                             140                                                                                  ##STR242##                                                                               ##STR243## H  182.5-184.0                                                                          3440, 1710, 1620, 1150                                                                     --                             141                                                                                  ##STR244##                                                                               ##STR245## H  135.5-136.0                                                                          3330, 1690, 1510, 1110                                                                     --                             142                                                                                  ##STR246##                                                                              H           H  57.0-62.0                                                                            3335, 1700, 1615, 1420                                                                     -42.5° (C = 1.00,                                                       EtOH)     F                    143                                                                                  ##STR247##                                                                              CH.sub. 3   H  Amorphous                                                                            (neat) 3330, 1695, 1505,                                                                   -39.4° (C = 2.04,                                                       EtOH)     F                    144                                                                                  ##STR248##                                                                              CH.sub.2 CH.sub.3                                                                          H  Oily  (neat) 3360, 1695, 1615,                                                                   -34.8° (C = 1.00,                                                       EtOH)     F                    145                                                                                  ##STR249##                                                                               ##STR250## H  148.0-151.0                                                                          3305, 1695, 1620, 1600                                                                     -10.7° (C = 1.00,                                                       CHCl.sub.3)                                                                              F                    146                                                                                  ##STR251##                                                                              H           H  207.0-214.0                                                                          3485, 1715, 1605, 1490                                                                     -42.5° (C = 1.00,                                                       EtOH)     FG                   147                                                                                  ##STR252##                                                                              CH.sub.3    H  110.0-111.0                                                                          3440, 1705, 1560, 1100                                                                     -25.0° (C = 0.92,                                                       EtOH)     F                    148                                                                                  ##STR253##                                                                               ##STR254## H  187.5-188.0                                                                          3310, 1695, 1550, 1140                                                                     -15.0° (C = 1.20,                                                       EtOH)     F                    __________________________________________________________________________

EXAMPLE 149

N-(4-hydroxyphenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide was obtained in the same manner as in Example 58 from the compound obtained in Example 139.

Melting point: 115.0-°117.0° C.

IR (KBr) cm⁻¹ : 3385, 1695, 1515, 1140

EXAMPLE 150

In 2 ml of N,N-dimethylformamide was dissolved 0.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. To the resulting solution was added 0.012 g of 60% sodium hydride at 0°-5° C. The solution was subjected to reaction at 20°-25° C. for 30 minutes. To the reaction mixture was added 0.04 g of methyl iodide at 0°-5° C. The resulting mixture was subjected to reaction at 20°-25° C. for 12 hours. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=100/1) to obtain 30 mg of N-(1-methoxy-2-methylpropan-2-yl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.

IR (neat) cm⁻¹ : 3395, 1700, 1510, 1090

EXAMPLE 151

To 10 ml of dried tetrahydrofuran were added 0.36 g of N-(2-hydroxyethyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide, 0.39 g of triphenylphosphine and 0.26 g of diethyl azodicarboxylate. The resulting mixture was subjected to reaction at 20°-25° C. for 12 hours. The reaction mixture was introduced into a mixed solvent consisting of 20 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 0.13 g of 1-aziridinylcarbonyl-2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propane.

Melting point: 87.5°-88.0° C.

IR (KBr) cm⁻¹ : 3415, 1680, 1615, 1080 

What is claimed is:
 1. A triazole derivative represented by the formula (1) or its salt: ##STR255## wherein R¹ represents a substituted or unsubstituted phenyl or naphthyl group; R² represents a fluorine atom; and R³ represents a group of the formula ##STR256## in which R⁴ is a group of the formula ##STR257## (R⁷ and R⁸, which may be the same or different, are hydrogen atoms or substituted or unsubstituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, amino, C₁₋₁₀ alkoxy or hydroxyl groups), wherein the phenyl and naphthyl groups for R¹ ; the C₁₋₁₀ alkyl group for R² ; and the C₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, amino, C₁₋₁₀ alkoxy and hydroxy groups for R⁷ and R⁸ may each be substituted by at least one substituent selected from the group consisting of halogen atoms, unsubstituted or cyano-substituted C₁₋₄ alkyl groups, C₁₋₄ alkoxy groups, halo-C₁₋₄ alkoxy groups, C₁₋₄ alkylthio groups, C₁₋₄ alkoxycarbonyl groups, hydroxyl group, mercapto group, carboxyl group, amino group, N--C₁₋₄ alkylamino groups, N,N-di-C₁₋₄ alkylamino groups, cyano group, nitro group, halo-C₁₋₄ alkyl groups, unsubstituted or halogen-substituted phenyl groups, unsubstituted or halogen-substituted naphthyl groups, unsubstituted or halogen-substituted formyl groups, unsubstituted or halogen-substituted C₂₋₁₀ alkanoyl groups unsubstituted or halogen-substituted benzoyl groups and unsubstituted or C₁₋₁₀ alkyl-, C₃₋₈ cycloalkyl-, phenyl- or naphthyl-substituted carbamoyl groups.
 2. The triazole derivative or its salt according to claim 1, wherein each of the substituted phenyl or naphthyl group in the definition of R¹ ; and the substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, amino, C₁₋₁₀ alkoxy or hydroxyl group in the definitions of R⁷ and R⁸ has at least one substituent selected from the group consisting of halogen atoms, unsubstituted or cyano-substituted C₁₋₄ alkyl groups, C₁₋₄ alkoxy groups, halo-C₁₋₄ alkoxy groups, C₁₋₄ alkylthio groups, N,N-di-C₁₋₄ alkoxycarbonyl groups, hydroxyl group, mercapto group, carboxyl group, amino group, N--C₁₋₄ alkylamino groups, N,N-di-C₁₋₄ alkylamino groups, cyano group, nitro group, halo-C₁₋₄ alkyl groups, unsubstituted or halogen-substituted phenyl groups, unsubstituted or halogen-substituted naphthyl groups, unsubstituted or halogen-substituted formyl groups, unsubstituted or halogen-substituted C₂₋₁₀ alkanoyl groups and unsubstituted or C₁₋₁₀ alkyl-, C₃₋₈ cycloalkyl-, phenyl- or naphthyl-substituted carbamoyl groups.
 3. The triazole derivative or its salt according to claim 1, wherein each of the substituted phenyl or naphthyl group in the definition of R¹ ; alkyl group in the definitions of R² and R⁶ ; and the substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, amino, C₁₋₁₀ alkoxy or hydroxyl group in the definitions of R⁷ and R⁸ has at least one substituent selected from the group consisting of halogen atoms, C₁₋₄ alkyl groups, C₁₋₄ alkoxy groups, C₁₋₄ alkylthio groups, C₁₋₄ alkoxycarbonyl groups, hydroxyl group, mercapto group, carboxyl group, amino group, N--C₁₋₄ alkylamino groups, N,N-di-C₁₋₄ alkylamino groups, cyano group, halo-C₁₋₄ alkyl groups, unsubstituted or halogen-substituted phenyl groups, unsubstituted or halogen-substituted naphthyl groups, unsubstituted or halogen-substituted formyl groups, unsubstituted or halogen-substituted C₂₋₁₀ alkanoyl groups unsubstituted or halogen-substituted benzoyl groups and unsubstituted or C₁₋₁₀ alkyl-, C₃₋₈ cycloalkyl-, phenyl- or naphthyl-substituted carbamoyl groups.
 4. The triazole derivative or its salt according to claim 1, wherein R¹ represents a phenyl or naphthyl group which may be optionally substituted by a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a halo-C₁₋₄ alkoxy group; R² represents a fluorine atom; R³ represents a group of the formula ##STR258## in which R⁴ is a group of the formula ##STR259## (R⁷ and R⁸, which may be the same or different, are hydrogen atoms; C₁₋₁₀ alkyl groups which may be optionally substituted by a halogen atom, a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group, a C₁₋₄ alkoxycarbonyl group, a hydroxyl group, a mercapto group, a carboxyl group, an N,N-di-C₁₋₄ alkylamino group, a cyano group, a halogen-substituted phenyl group or a C₃₋₈ cycloalkyl-substituted carbamoyl group; C₂₋₁₀ alkenyl groups; C₂₋₁₀ alkynyl groups; C₃₋₈ cycloalkyl groups which may be optionally substituted by a C₁₋₄ alkyl group or a halogen-substituted phenyl group; phenyl groups which may be optionally substituted by a halogen atom, an unsubstituted or cyano-substituted C₁₋₄ alkyl group, a halo- C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a hydroxyl group or a cyano group; amino groups which may be optionally substituted by a halogen-substituted benzoyl group; hydroxyl group; C₁₋₄ alkoxy groups or a phenyl-substituted carbamoyl group.
 5. The triazole derivative or its salt according to claim 1, wherein R¹ represents a phenyl group which may be optionally substituted by a halogen atom; R² represents a fluorine atom; and R³ represents a group of the formula ##STR260## in which R⁴ is a group of the formula ##STR261## (R⁷ and R⁸, which may be the same or different, are hydrogen atoms; C₁₋₁₀ alkyl groups which may be optionally substituted by a halogen atom, a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group, a C₁₋₄ alkoxycarbonyl group, a hydroxyl group, a mercapto group, a carboxyl group, an N,N-di-C₁₋₄ alkylamino group, a cyano group, a halogen-substituted phenyl group or a C₃₋₈ cycloalkyl-substituted carbamoyl group; C₂₋₁₀ alkenyl groups; C₂₋₁₀ alkynyl groups; C₃₋₈ cycloalkyl groups which may be optionally substituted by a C₁₋₄ alkyl group or a halogen-substituted phenyl group; phenyl groups which may be optionally substituted by a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a hydroxyl group or a cyano group; amino groups which may be optionally substituted by a halogen-substituted benzoyl group; hydroxyl group; C₁₋₄ alkoxy groups).
 6. The triazole derivative or its salt according to claim 5, wherein R³ represents a group of the formula: ##STR262## in which one of R⁷ and R⁸ is a hydrogen atom and the other is a hydrogen atom; an C₁₋₁₀ alkyl group which may be optionally substituted by a halogen atom, a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group, a C₁₋₄ alkoxycarbonyl group, a hydroxyl group, a mercapto group, a carboxyl group, an N,N-di-C₁₋₄ alkylamino group, a cyano group, a halogen-substituted phenyl group or a C₃₋₈ cycloalkyl-substituted carbamoyl group; an C₂₋₁₀ alkenyl group; an C₂₋₁₀ alkynyl group; a C₃₋₈ cycloalkyl group which may be optionally substituted by a C₁₋₄ alkyl group or a halogen-substituted phenyl group; a phenyl group which may be optionally substituted by a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a hydroxyl group or a cyano group; an amino group which may be optionally substituted by a halogen-substituted benzoyl group; a hydroxyl group or a C₁₋₄ alkoxy group.
 7. The triazole derivative or its salt according to claim 6, wherein R¹ represents a halogen-substituted phenyl group and R² represents a fluorine atom.
 8. The triazole derivative or its salt according to claim 7, wherein one of R⁷ and R⁸ is a hydrogen atom and the other is a hydrogen atom, a C₁₋₄ alkyl group or a cyclopropyl group.
 9. The triazole derivative or its salt according to claim 7, wherein the halogen-substituted phenyl group is a 2,4-difluorophenyl group or a 2-chloro-4-fluorophenyl group.
 10. The triazole derivative or its salt according to claim 9, wherein one of R⁷ and R⁸ is a hydrogen atom and the other is a hydrogen atom, a methyl group or a cyclopropyl group.
 11. N-methyl-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 12. (-)-N-methyl-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 13. 3-(2,4-Difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 14. (-)-3-(2,4-Difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 15. 3-(2-Chloro-4-fluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 16. (-)-3-(2-Chloro-4-fluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 17. N-methyl-3-(2-chloro-4-fluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 18. (-)-N-methyl-3-(2-chloro-4-fluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 19. N-cyclopropyl-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 20. (-)-N-cyclopropyl-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide or its salt.
 21. An antifungal composition comprising an effective amount of a triazole derivative as in any of claims 1-19 or 20 and a pharmaceutically acceptable carrier, excipient or diluent. 